Intravitreal injection has become the standard of care for drug delivery to the back of the eye. While this method administers drug to the eye, it does not target drug delivery within the eye to the sites of therapeutic action, specifically in the choroid and retina. This leads to inefficient use of the drug and possible side effects at off-target sites, especially in the anterior segment. Moreover, repeated intravitreal injections are associated with side effects including endophthalmitis, retinal detachment, and cataracts. In this proposal, we seek to target drug delivery to the sites of therapeutic action in choroid and retina by injecting drugs into the suprachoroidal space (SCS) using a microneedle. The SCS is a potential space between sclera and choroid that can be accessed selectively and in a minimally invasive way using a microneedle measuring hundreds of microns long. Drug targeted into the SCS bathes the choroidal surface and adjacent retina, rather than distributing drug throughout the posterior segment, as occurs after intravitreal injection. A few studies, mostly from our laboratories, have demonstrated feasibility of drug delivery to SCS. This multidisciplinary project will provide the first in-depth study of suprachoroidal drug delivery targeted using microneedles and thereby develop novel drug delivery technologies that set the stage for clinical translation. This project will study drug delivery to the SCS to improve treatment of choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD), which is the leading cause of blindness in the elderly. We will study administration of bevacizumab, a macromolecular antibody drug in widespread clinical use for this indication, and pazopanib, a small-molecule, anti-angiogenic drug under investigation to treat CNV. Our preliminary studies indicate that drug administration to the SCS offers superior tissue-specific targeting to the posterior segment and especially to the choroid and adjacent retina. Based on these findings, our long- term objective is to develop minimally invasive, targeted drug delivery methods that are superior to intravitreal injections, in order to enhance drug efficacy, while minimizing drug and injection-related side effects in treating CNV. In this study, we will test the hypothesis that suprachoroidal drug delivery offers a safe route of administration for sustained and effective therapy of posterior segment diseases such as CNV. The project has three specific aims: 1) Design and fabricate a minimally invasive microneedle device and determine its effect on targeted suprachoroidal delivery. 2) Determine the effect of drug physicochemical properties and sustained- release formulations on drug pharmacokinetics and biodistribution in the tissues of the back of the eye after suprachoroidal delivery. 3) Determine the efficacy and safety of suprachoroidal delivery of a small molecule drug and a macromolecule drug for sustained-release treatment of choroidal neovascularization. In addition to improving CNV therapy, the outcomes of this project will provide innovative targeted solutions for treating other posterior segment disorders including diabetic retinopathy, dry AMD, retinitis pigmentosa, and uveitis.